Polymorphs, Solvatomorphs, Hydrate, and Perhydrate of Dabrafenib

Crystal form screening of the anticancer drug dabrafenib (DBF) was performed using a wide range of nonpolar aprotic, polar aprotic, and polar protic solvents. Extensive crystallization in these solvent systems produced three crystal forms (I, II, and III) of the drug, a monohydrate, an isomorphous peroxo solvate, and eight different solvates with ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, 1,1,2,2-tetra-chloroethane, tetrachloroethylene, benzene, and anisole of DBF. Surprisingly no solvates were crystallized with the alcohol solvents attempted. The novel crystalline forms were characterized by single-crystal X-ray diffraction (SC-XRD) or structure determi-nation from powder data (SDPD). The neutral drug derived from the mesylate salt of DBF by neutralization (form Ia) and the crystallized form I exhibited almost a similar powder XRD line pattern but their differential scanning calorimetry (DSC) thermograms comparison showed significant differences. Thus, the structure of microcrystalline powder form Ia was solved from SDPD reflections and showed the same molecular packing but different conformational strain compared to form I (structure by SC-XRD). The relative stability of the drug polymorphs was calculated using dispersion-corrected density functional theory with an intramolecular conformational energy correction. The calculations suggest that form II is the most stable polymorph and form III, form I, and form Ia are progressively less stable. Residual water content analysis of the isomorphous peroxosolvate showed that it is a mixed hydrate/peroxosolvate with similar to 9.5% water occupancy quantified by 31P nuclear magnetic resonance analysis of the peroxosolvate content using triphenylphosphine oxide. The supramolecular analysis and molecular packing of DBF crystal forms suggest that the molecule has a propensity to form solvates with aprotic solvents and more specifically with chlorohydrocarbons. With its high molecular flexibility, prolific solvate potential, and drug polymorphism, the present work opens the opportunity for further solid-form landscape study of the popular anticancer drug DBF.